This invention relates to synthetic thyroid hormones, compositions and methods for treating elevated intraocular pressure and glaucoma.
Glaucoma afflicts approximately two million people in the United States and about 15 million people worldwide. Approximately two percent of the population over 35 suffers from some form of glaucoma and it accounts for approximately 12% of all cases of blindness. Despite its easy diagnosis, therapies to lower intraocular pressure (IOP) in patients with glaucoma are frequently inadequate. Use of topical and oral medicines to lower intraocular pressure is often limited by side effects of the drugs. In other cases, use of medical therapy to treat glaucoma is not successful in lowering intraocular pressure sufficiently to prevent progressive damage to the optic nerve.
Consequently, there is a need for methods, compounds and compositions for treating glaucoma and other medical conditions of the eye or epithelium.
Before the invention described herein, changes in IOP due to systemic changes in thyroid hormone levels, were postulated to be indirect, or if direct, such thyroid hormone-induced changes in IOP were thought to be mediated through the adrenergic a or, receptors located in the eye. Aspects of the present invention now recognize for the first time an important role of thyroid hormone receptors in eye physiology. Eye thyroid receptors provide an opportunity to directly mediate thyroid hormone effects in eye cells. In particular, thyroid receptors of human trabecular meshwork (xe2x80x9cHTMxe2x80x9d) cells can potentially mediate the amount of extracellular hyaluronic acid (xe2x80x9cHAxe2x80x9d) maintained by HTM cells, which in turn can affect aqueous humor outflow.
The present invention recognizes that cells containing thyroid hormone receptors and cellular processes involved in GAG production would be useful components of in vitro or in vivo methods for identifying compounds that are useful as therapeutics, such as compounds that modulate glycosaminoglycans (xe2x80x9cGAGxe2x80x9d) production. The method of identifying compounds useful for therapeutics comprises: 1) contacting a compound with cells that secrete GAG, such as trabecular meshwork cells, and 2) detecting the binding of the compound to the cells, wherein the compound has concentration of 10 micromolar or less.
In addition the present invention recognizes that thyroid hormones and synthetic thyroid hormones (STHs) can directly modulate GAG production or HA secretion from cells, such as trabecular meshwork cells. Methods of the invention, consequently, are directed to modulating GAG production or HA secretion using compounds, especially STHs, that reduce the amount or activity of such substances or cellular processes in the desired cells or tissues. Preferably, such cells will be trabecular meshwork cells, ciliary cells of the eye, endothelial cells of the eye, non-eye endothelial cells, and fibroblasts of skin and internal organs. In most instances non-systemic application of a STH is preferred, although STHs can be administered systemically as well.
The present invention also provides for a method of treating glaucoma comprising administering to an eye in need thereof an ophthalmically effective amount of a synthetic thyroid hormone to the eye. Modes of administration include topical, intraocular implantation or injection, and systemic. Preferably administration of a STH to the eye is topical administration with an eye compatible pharmaceutical carrier or non-systemic administration via a surgically implantable or injectable device, which may comprise a biodegradable or non-biodegradable polymer capable of sustained release of the STH intraocularly. Ocular inserts containing STH in a sustained release polymer may also be used.